Wednesday , April 14 2021

the end of the tunnel soon

Ambitious research on HIV vaccine development began in 1983 by Françoise Barré-Sinoussi shortly after the discovery of the virus leading to the AIDS epidemic. Lack of effective treatment for the development of an emergency vaccine.

The United States Health Minister Margaret Heckler has announced that a vaccine will be available in the first two years of 1984. A vision shared by others – the virus had just been discovered and the complexity of its physiopathology was then far from reaching its true size. Moreover, in the 1970s and 1980s, the development of vaccines based on viral or bacterial proteins and not solely based on all microorganisms strengthened this optimism.

However, the efforts of researchers and doctors would face many difficulties over many years. 34 years later, the development of a prophylactic vaccine remains a priority of HIV research. But today, the end of the tunnel seems closer than ever.

Lymphocytes, large players in immunity

There are three lines of defense of our body against pathogenic microorganisms and especially viruses. The first is the barrier of skin and mucous membranes. If crossed, the invader then looks at natural immunity based on cells that can recognize foreign agents. Identify the components (sugars, proteins, etc.) present on the surface called antigens. This immunity is not specific to a particular substance, it attacks everything that is not the body. It also prepares the third line of defense, the acquired immunity. This is the second stimulated by inoculation.

Acquired immunity is more subtle than innate immunity, and most importantly, specific: agents can recognize and attack a particular microorganism. They also retain the memory of previous encounters, which allows them to react more quickly in the case of a new invasion of the same pathogen.

Acquired immunity is complex, but the main actors are lymphocytes, a class of specific white blood cells. There are several types, but B lymphocytes (LB) and CD8 + T-lymphocytes (LT CD8) play an important role. First, the antibodies make molecules that can bind molecules to an invader specifically to protect and neutralize itself. Another role of the antibodies is to attract the attention of the cells of the immune system which will destroy the viruses covered in this way. Meanwhile, CD8 LTs prevent the spread of infection by directly destroying viruses infected cells.

The action of these two lymphocyte categories is stimulated by a third type of lymphocytes, CD4 + LT lymphocytes (LT CD4), stimulating them, and they play the role of the conductors of the acquired immune response in a particular way. These CD4 + T cells are the primary target of HIV, which destroys them and makes it very difficult to establish an effective immune response.

How does acquired immunity work?

Train your body to defend yourself

Immunization is the immune response of large maneuvers in military training. It simulates an infection by convincing the body that its invader passed lines to trigger an immune response. In this way, the body will actually react more quickly when it encounters the relevant microbes.

The vaccines used may include fragments (protein vaccines) of the germ (s) to which protection is desired, all microbes killed (inactivated vaccines), or live vaccines of these microbes (live vaccines). attenuated).

Live attenuated vaccines stimulate the production of both antibody and stimulation of CD8 LT by stimulating the closest immune protection to those caused by natural infection. However, if their use regains virulence of the microorganisms they contain, the risk of causing an infectious vaccine-derived disease is low. For obvious security reasons, such a vaccine cannot be used in the case of HIV.

Therefore, it was necessary to resort to subsections to obtain the optimal immune response of the same type. But in the way of researchers stopped several obstacles.

HIV, difficult virus

One of the main problems facing scientists working in the development of HIV vaccine is the extreme diversity of the virus. There are two main types of viruses: HIV1 and HIV2 are divided into different groups according to their origin (each group can be subdivided again).

HIV2 (divided into nine groups from A to B) is mostly found in West Africa and very small, in the inhabitants of western countries and India (represented in France) . In 2% of infections. HIV1 can be divided into four groups: M (Major, responsible for the majority of HIV infections), O (Outlier), N (non-M, O), P (finally described in 2009). ).

The HIV genome consists of RNA, not DNA. Like all RNA viruses, it multiplies itself to make many mistakes. Reveals a number of slightly different variants. This leads to a very important viral diversity not only among infected individuals but also within each. Only one infected patient can carry millions of different variants than the variation that occurs during the global influenza epidemic! But the second one requires the development of a new vaccine every year …

The second major problem in the development of a vaccine is that HIV infection does not necessarily constitute a protection. Indeed, the antibodies produced after HIV infection are not adequately protective. Furthermore, CD8 LTs can control the replication of the virus, but not the infection. Finally, suş natural in immunity that can be achieved does not prevent super-infections by other strains of HIV.

In the absence of treatment, HIV-infected patients will inevitably progress towards the AIDS stage and will not be considered a particular small group of patients known as the elite controller. The latter, which represents less than 1% of the population of infected individuals, has CD8 CD8, which can destroy the infected CD4 LT, and therefore includes infection.

First milestones of vaccine research

A French team in 1987 tested a live attenuated vaccine containing a vaccinia virus modified to make an HIV1 protein. It has been recently recognized that this technology is allowed to induce the synthesis of antibodies and stimulate CD8 LT. Unfortunately, the tests failed.

Almost all available vaccines can be used against other infections that are based on stimulating antibodies, preventing the pathogen from entering the patient's cells. The first anti-HIV vaccine strategies aimed at the induction of such neutralizing antibodies. However, in the case of HIV, these antibodies are effective against only a few virus strains. They cannot neutralize the abundance of variants in a patient's body.

The first phase 3 clinical trial of HIV vaccines (studies that evaluated the efficacy of a drug) was expected from 1998 to 2002. People called AIDSVAX participated in more than 7,000 participants. North America, the Netherlands and Thailand.

Inspired by the efficacy of hepatitis B vaccine based on proteins found only in the HIV envelope, these HIV vaccines were protein vaccines containing HIV envelope protein (from two sub-types). HIV1 is common in geographical regions where studies are conducted. However, these tests did not provide protection against infection.

A year later, another phase 3 trial, RV144, started in Thailand. From 2003 to 2009, with more than 16,400 participants, they took the HIV protein used in AIDSVAX and produced other HIV proteins with the canary virus virus, a harmless viral vector.

For the first time, this approach provided partial protection against HIV infection. The results, published in 2009, revealed that the vaccine retained 31.2% of participants.

The most promising current strategies

If the results of the RV144 trial were encouraging, they had three problems:

  • They were based on only one experiment and the protection given was short-lived;

  • protection was directed to a priority only against the subtype of the virus;

  • Such a strategy did not induce broad-spectrum neutralizing antibodies capable of blocking all available HIV types.

The HVTN702 test was established in South Africa to find an answer to the first point. This is based on the same strategy as the RV144 study, but vaccines are produced from a predominant HIV strain in Africa and an additional vaccine injection is provided one year after the first injection to increase vaccine time. The establishment of the immune response in November 2017, the results are expected to be held in January 2022.

Researchers have developed "mosaic" vaccines to try to address the lack of diversity in conservation. The vaccine strategy remains substantially the same using a viral vector and envelope proteins using two different vaccines. However, the viral vector no longer produces a protein derived from a single HIV strain, but does not produce protein fragments from several strains. They were able to induce a broader immune response by researchers through bioinformatics.

This approved strategy in non-human primate models has led to the establishment of an activity trial. HVTN 705 / HPX2008 The dubbing titled "Imbokodo" began in November 2018. In sub-Saharan Africa (mostly South Africa), it is expected that 2,600 women will take part in five countries and end in 2022.

Both strategies are likely to lead to success rates of about 50%. This may seem weak, but having a 50% effective vaccine will be a big step at both the individual and population level. In fact, vaccinated populations will be those in areas of high endemicity or those at risk (MSM, prostitutes …). The impact of such a vaccine on the evolution of the outbreak was very well modeled, in particular by the IAVI consortium (International AIDS Vaccine Initiative).

Hair of neutralizing antibodies

It is important that these advances do not allow neutralizing antibodies to cause a broad spectrum. This is the only way to provide highly effective protection at the individual level.

If such a vaccine had been considered a chimera for a long time, the latest data indicates that this is not the case. Studies in the United States in groups at risk showed that approximately 1% of HIV-infected individuals were able to detect broad spectrum neutralizing antibodies.

Despite their existence, the virus continues to multiply in the body of these patients. However, it is noted that when these antibodies are purified, they can block infection of 90% to 95% HIV1 strain in the laboratory.

This is important because in the long term, if an HIV-infected individual needs to defend against many different viruses, it is initially infected with a single virus. If a vaccine can induce such antibodies, it can be from 90 to 95% preservative!

Strategies are currently underway in animal trials to induce these antibodies. They are very complex and their clinical development in humans is far less developed than previously described.

Other anti-HIV vaccine strategies have been developed, in particular, based on the induction of a CD8 LT response. Unfortunately, most people have proven ineffective in clinical trials.

With regard to CD8 LTs, only one piece seems promising, but has been evaluated only in non-human primates and provided 50% protection.

HIV vaccine research is still very active and the results of two ongoing Phase 3 clinical trials are likely to be expected.

Recently, the discovery of the presence of broad-spectrum neutralizing antibodies in some patients is a great hope for the future development of an individual-level vaccine.

Regardless of the results, the information obtained from this HIV study will improve the vaccine design against other complex pathogens that are highly capable of mutating, such as viruses. Flu

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